[Thyroid papillary carcinoma].
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Biomarkers↗
Biomedical subjects
Toru Takano
Publications and source records attributed to Toru Takano.
Fetal cell carcinogenesis of the thyroid: theory and practice.
A novel hypothesis of thyroid carcinogenesis, the "fetal cell carcinogenesis" hypothesis, in which cancer cells are derived from the remnants of three types of fetal thyroid cells, instead of normal thyroid follicular cells, is proposed. In this hypothesis, thyroid cancer cells are generated from fetal cells by proliferation without differentiation and oncogenes play an oncogenic role by preventing fetal cells from differentiating. This hypothesis explains well the clinical and biological features and recent molecular evidence of thyroid carcinoma. It underscores the importance of clarifying the molecular mechanism of thyroid development and the identification of fetal thyroid cells, especially thyroid stem cells (TSCs), since such data will lead to better understanding of thyroid carcinoma and other thyroid diseases.
Animals↗
Thyroxine to triiodothyronine hyperconversion thyrotoxicosis in patients with large metastases of follicular thyroid carcinoma.
OBJECTIVE: We experienced two cases of follicular thyroid carcinoma with distant metastases, which showed high levels of free triiodothyronine (T(3)) while free thyroxine (T(4)) levels remained in the low or normal range. In this report, we described the detail of these cases and examined the cause of T(3) thyrotoxicosis. DESIGN: In one of the cases, quantitative measurement of types I and II iodothyronine deiodinase mRNAs was performed using a surgically dissected tissue from the primary tumor and a distant metastasis. MAIN OUTCOME: In the both tissues, types I and II iodothyronine deiodinase mRNAs were expressed in the same level as in the normal thyroid tissues. CONCLUSION: These results suggest that T(3) thyrotoxicosis in our patients was caused by hyperconversion of administered levothyroxine to T(3). In the follow-up of patients with distant metastases of follicular carcinoma, not only free T(4), but also free T(3) should be tested to avoid the excessive administration of levothyroxine.
Adenocarcinoma, Follicular↗
Thrombospondin 1 mRNA as a candidate for a marker to detect thyroid-derived fibroblasts in fine needle aspiration biopsy of the thyroid.
Possible interference of fibroblasts is suggested in aspiration biopsy nucleic acid diagnosis (ABND). However, detection of fibroblasts in the aspirates is difficult, because the gene expression profiles of thyroid malignancies and fibroblasts are much alike in many aspects. To identify a specific marker for thyroid-derived fibroblasts, the data of the serial analysis of gene expression (SAGE) were compared to screen differentially expressed genes between fibroblasts and thyroid normal and tumor tissues. In the SAGE data, 5 genes were identified to be differentially expressed. Among these, thrombospondin 1 (TSP-1, THBS1) mRNA was the most differentially expressed. Further, the overexpression of TSP-1 mRNA in fibroblasts was confirmed by real-time RT-PCR analysis using 73 thyroid normal and tumor tissues and 7 cultures of thyroid-derived fibroblasts. These results suggest that TSP-1 mRNA is a possible marker for contamination of thyroid-derived fibroblasts.
Biomarkers↗
Tensin3 is a novel thyroid-specific gene.
Thyroid-specific genes, such as thyroid peroxidase, thyroglobulin, Na+/I- symporter and thyroid-stimulating hormone receptor, play fundamental roles in thyroid function and relate to many pathological conditions. Using sequence specific-differential display, we detected three genes that showed higher expression levels in normal thyroid tissues than in thyroid tumor tissues. After subcloning and sequencing analysis, one of the genes was revealed to be tensin3. The expression level of tensin3 was examined with real-time quantitative PCR analysis. Its expression levels were more depressed in thyroid tumor tissues than in normal thyroid tissues. The decrease was even more evident in two anaplastic carcinomas. High and moderate levels of tensin3 mRNA expression were observed in the thyroid and placenta respectively. Tensin3 mRNA was expressed only in low levels in other tissues, such as the brain, heart, lung, liver, pancreas, kidney, skeletal muscle, white blood cells and prostate. These results show that tensin3 is a novel thyroid-specific gene and further investigations may reveal its relation to thyroid function or thyroid disease.
Humans↗
Differentiation of follicular thyroid adenoma from carcinoma by means of gene expression profiling with adapter-tagged competitive polymerase chain reaction.
OBJECTIVE: Since preoperative differentiation between follicular thyroid adenoma (FTA) and carcinoma (FTC) remains very difficult, the purpose of this study was to identify the genes differentially expressed in FTA and FTC in order to construct a diagnostic system based on such genes for differentiation of FTA and FTC. METHODS: Gene expression profiles of 45 FTAs and 22 FTCs were analyzed by means of adapter-tagged competitive polymerase chain reaction (ATAC-PCR) with 2,516 genes (learning set). The genes differentially expressed in FTAs and FTCs were then used to construct a diagnostic system based on the weighted-voting algorithm. In addition, a validation study of this diagnostic system was conducted using 12 FTAs and 6 FTCs (validation set). RESULTS: The diagnostic system for differentiation of FTA and FTC, constructed with the aid of the learning set samples, was based on 60 genes differentially expressed in FTA and FTC, which included several genes previously identified as overexpressed in FTC (DPP4, KRT19 and IGFBP3) or FTA (trefoil factor 3 and thyroid peroxidase). The leave-one-out cross-validation study showed that the accuracy of this diagnostic system was as high as 90% (sensitivity: 77.3% and specificity: 95.6%), and was confirmed by the validation study (diagnostic accuracy: 83.3%; 95% confidence interval: 62.8-95.4%, sensitivity: 66.7% and specificity: 91.2%). CONCLUSIONS: This diagnostic system using the ATAC-PCR assay is expected to be clinically useful for preoperative differentiation between FTA and FTC since ATAC-PCR can be used for the small amount of RNA obtained from fine needle aspiration biopsy.
Adenoma↗
Decreased relative expression level of trefoil factor 3 mRNA to galectin-3 mRNA distinguishes thyroid follicular carcinoma from adenoma.
The expression level of trefoil factor 3 (TFF3) mRNA is a marker for distinguishing thyroid follicular adenomas from carcinomas. However, when measuring the expression level of TFF3 mRNA in fine needle aspiration biopsies, an appropriate internal control mRNA, of which expression is restricted in thyroid epithelial--derived cells, is necessary, since they are often contaminated with a considerable number of blood cells, which do not express TFF3 mRNA. In this study, we evaluated the efficiency of molecular-based diagnosis of thyroid follicular carcinoma by measuring the relative expression of TFF3 mRNA by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using galectin-3 mRNA as an internal control. The TFF3/galectin-3 mRNA ratio (T/G ratio) was measured in 54 follicular adenomas and 29 follicular carcinomas. It was markedly decreased in 7 follicular carcinomas of widely invasive type and with evident distant metastases. When the cutoff point was set at 16.0 by a receiver operator characteristic curve, the TG ratio showed good agreement with the pathological diagnosis [kappa=0.55; 95% confidence interval (CI), 0.34-0.77]. This agreement was better when the pathologically questionable cases were excluded (kappa=0.72; 95% CI, 0.49-0.95). Quantification of the T/G ratio may be a useful tool for the distinction between follicular adenomas and carcinomas, which is the most difficult in thyroid pathology.
Adenocarcinoma, Follicular↗
Fetal cell carcinogenesis: a new hypothesis for better understanding of thyroid carcinoma.
Modern advances in molecular technology have given us the chance to establish a new insight into thyroid carcinogenesis. Gene expression in thyroid malignancies usually reveals highly consistent profiles, which leads to questioning of the classic concept of multistep carcinogenesis, in which cancer cells are produced from well-differentiated benign cells by transformation caused by accumulating damage to their genome. We propose a novel hypothesis of thyroid carcinogenesis, the fetal cell carcinogenesis hypothesis, in which cancer cells are derived from the remnants of three types of fetal thyroid cells, instead of normal thyroid follicular cells. This hypothesis explains well the clinical and biologic features and recent molecular evidence of thyroid carcinoma. It suggests the importance of clarifying the molecular mechanism of thyroid development and the identification of fetal thyroid cells, especially thyroid stem cells (TSCs), because such data will lead to better understanding of thyroid carcinogenesis and thyroid regeneration.
Adult↗
Two-phase CT pulmonary angiography for detection of hilar pulmonary thromboembolism.
PURPOSE: To assess the usefulness of two-phase CT pulmonary angiography (CTPA) for patients with suspected pulmonary thromboembolism (PE). MATERIALS AND METHODS: Forty-four patients (in 48 studies) underwent two-phase CTPA. Fifteen sec after the injection of contrast material, an entire thorax scan was performed, and in the second phase the hilar territory was rescanned after a 15-sec delay. In the first phase, 25 subjects were scanned cranio-caudally (group A), and 23 caudal-cranially (group B). The mean attenuation values of the main pulmonary artery (MPA) and the ascending aorta (Ao) were measured. Perivenous artifacts in the right pulmonary artery (RPA) were also graded using a 4-point scale. RESULTS: The mean attenuation values in the MPA and Ao were higher in the first phase than in the second phase. The perivenous artifact scores at the first phase in groups A and B were severe in 12 and 15, moderate in 8 and 7, minimal in 4 and 1, and none in 1 and 0. The scores at the second phase were none in all cases. CONCLUSION: Two-phase CTPA produced good opacification of the RPA without major perivenous artifact and proved useful in the detection of PE in these areas.
Adult↗
Detection of monoclonality of the immunoglobulin heavy chain gene in thyroid malignant lymphoma by vectorette polymerase chain reaction.
Distinguishing between thyroid malignant lymphoma and lymphocytic thyroiditis (Hashimoto's thyroiditis) is quite difficult and problematic. B cell lymphomas display clonal Ig heavy-chain (IgH) gene rearrangement, and Southern blot hybridization (SBH) is often used for detection of the monoclonality of the IgH gene. However, SBH is often problematic because it requires a large volume of samples. We examined the efficiency in detecting the monoclonality of IgH gene in thyroid malignant lymphomas by vectorette PCR, which we started with only 200 ng of genomic DNA. Monoclonality was detected in 36 of 47 (76.6%) malignant lymphomas, whereas it was not detected in 10 samples of tissue of Hashimoto's thyroiditis. The sensitivity was almost the same as that with SBH in which monoclonality was detected in 33 of 45 (73.3%) malignant lymphomas. These results suggest that vectorette PCR may be a substitute for SBH, and because it requires only a small volume of samples, it may be used in the analysis of aspiration biopsies.
Base Sequence↗
Serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and their relation to cytokine production during and after normal pregnancy.
BACKGROUND: Since dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have been suggested to have immunoregulatory effects, changes in the levels of these substances during and after pregnancy might affect the maternal immune system. We examined serum concentrations of DHEA and DHEAS, and cytokine production during pregnancy and after delivery. METHODS: The subjects were 73 normal pregnant, 76 normal postpartum and 30 normal non-pregnant women. Whole-blood was stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin and the levels of cytokines in the supernatant were measured using enzyme-linked immunosorbent assay (ELISA). DHEA and DHEAS were measured using ELISA and gas chromatography-mass spectrometry (GC-MS), respectively. RESULTS: The serum DHEA levels increased in the first and in the second trimesters and decreased after delivery until 11 months postpartum. DHEAS levels were decreased in the second and in the third trimesters and returned to non-pregnant levels after pregnancy. All measured cytokines (IFN-gamma, IL-2, IL-4 and IL-10) were decreased during pregnancy and subsequently increased postpartum. We found significant negative correlations between DHEA and cytokine levels. CONCLUSIONS: Increase of serum DHEA in the first and the second trimesters may suppress immune reaction during pregnancy, while a decrease of DHEA after delivery may induce postpartum enhancement of the maternal immune system. DHEA may be involved in modifying the maternal immune responses during and after pregnancy.
Adult↗
Serum concentrations of androstenediol and androstenediol sulfate, and their relation to cytokine production during and after normal pregnancy.
Since it is known that androstenediol (ADIOL) has potent immunoregulatory effects, changes in ADIOL levels during and after pregnancy might affect the maternal immune system. We examined serum concentrations of ADIOL and androstenediol 3-sulfate (ADIOLS) together with IFN-gamma and IL-4 production levels during pregnancy and after delivery up to 10-11 months postpartum. The subjects were 73 normal pregnant, 76 normal postpartum, and 28 normal non-pregnant women. ADIOL and ADIOLS were measured using EIA and GC/MS, respectively. The cytokine levels in the supernatant of whole-blood cultures stimulated with phorbol 12-myristate 13-acetate and ionomycin were measured using ELISA. ADIOL levels significantly decreased compared to non-pregnant levels in the first trimester (P < 0.05) and were reversed in the third trimester (P < 0.05). After pregnancy, ADIOL levels gradually declined, and a significant decrease was observed at 10-11 months postpartum (P < 0.05). ADIOLS levels were significantly lower in the third trimester (P < 0.05) and significantly higher at the first month postpartum (P < 0.001) compared to non-pregnant women. IFN-gamma and IL-4 levels decreased during pregnancy and subsequently increased postpartum. On the other hand, we found significant negative correlations between ADIOL concentrations and production levels of IFN-gamma (P < 0.05) or IL-4 (P < 0.05). These findings suggest that ADIOL may be involved in modifying the maternal immune response during and after pregnancy.
Adult↗
Fetal cell carcinogenesis of the thyroid: a hypothesis for better understanding of gene expression profile and genomic alternation in thyroid carcinoma.
Since the 1980s, cancer cells have been considered to be generated from well-differentiated benign cells by transformation caused by accumulating damage in their genomes. However, recent progress in gene expression analysis in thyroid malignancies has raised the possibility of another model of thyroid carcinogenesis. We propose a novel hypothesis of thyroid carcinogenesis, the fetal cell carcinogenesis hypothesis, in which cancer cells are derived from the remnants of fetal thyroid cells, instead of from normal thyroid follicular cells. This hypothesis explains well the clinical and biological features and recent molecular evidence of thyroid carcinoma. It suggests the importance of clarifying the molecular mechanism of thyroid development and the identification of fetal thyroid cells such as thyroid stem cells (TSCs), since such data will lead to a better understanding of thyroid carcinogenesis and thyroid regeneration.
Carcinoma, Papillary, Follicular↗
Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma is an aggressive neoplasm and resistant to all sorts of treatment due to its rapid growth and invasive potential. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor modulating variety of biological properties, such as regulating of adipogenesis, inhibition of cancer cell proliferation or differentiation of tumor cells. The purpose of this study was to evaluate the possibility for the therapeutic effect of PPARgamma ligands against anaplastic thyroid tumor in vitro. Expressions of the PPARc gene and protein were examined in 5 human anaplastic carcinoma cell lines (MSA, IAA, ROA, K119 and KOA-2). We next evaluated the effects of PPARgamma ligands (Thiazolidinedione, Prostaglandin J2 and RS1303) on proliferation, differentiation, apoptosis and invasion. Five cell lines showed higher level of the PPARc gene and protein expression than papillary thyroid carcinoma. PPARgamma ligands inhibited cell proliferation by inducing apoptosis instead of differentiation in dose-dependent manner. PPARgamma ligands also down regulated the invasive potential of 5 cell lines. The inhibitory effect of proliferation or invasion was prominent in 3 cell lines, which exhibited higher expression level of the PPARc gene or protein. Our results indicated that PPARgamma ligands modify malignant potential of anaplastic carcinoma cell lines altering growth or invasive properties, suggesting that PPARgamma could be potentially the novel molecular target for human thyroid anaplastic carcinoma.
Antineoplastic Agents↗
[Differential diagnosis of hepatitis: development of new laboratory tests for autoimmune hepatitis and progress in pathophysiology].
Liver dysfunction has been found in 8.1% of postpartum women in the general population. This dysfunction was speculated to be developed by postpartum aggravation of subclinical autoimmune hepatitis. Therefore, we developed two methods for detection of autoantibodies to liver-specific antigens: an ELISA for anti-liver-specific arginase antibodies, and a highly sensitive radioligand assay for anti-CYP2D6 antibodies. Basic examinations of dilution curve, inhibition study and reproducibility were satisfactory for clinical application in both assays. Anti-arginase antibodies and anti-CYP2D6 antibodies were found in 28.6% and 42.6% of patients with autoimmune hepatitis, respectively. There was no correlation between the two autoantibodies and thus, combined use of these antibodies detects 55.3% of autoimmune hepatitis. Autoimmune hepatitis exists frequently when we include mild cases.
Arginase↗
[Molecular-based diagnosis of thyroid carcinoma: germ-cell carcinogenesis and aspiration biopsy nucleic acid diagnosis(ABND)].
Recent data have shown the existence of specific changes in mRNAs in thyroid carcinomas. It has not been clarified, however, why these changes clearly distinguish benign tissues from carcinomas, while genomic alternation such as mutations in the RAS or P53 genes do not. Further, the widely believed hypothesis, multi-step carcinogenesis, does not explain some clinical and experimental evidence of thyroid carcinomas. Considering these facts, we propose a new idea for thyroid carcinogenesis called "germ-cell carcinogenesis", in which cancer cells are derived from the remnant of fetal thyroid germ cells(thyroblasts) instead of normal thyroid follicular cells. Utilizing such mRNAs, we have established a new method for preoperative molecular-based diagnosis of thyroid carcinomas, Aspiration Biopsy Nucleic Acid Diagnosis(ABND). ABND allows us to perform preoperative nucleic acid analyses of the tumors by extracting RNAs or DNAs from tumor cells obtained by fine needle aspiration biopsies(FNABs). Pathological diagnosis of thyroid follicular carcinoma is quite difficult, and the establishment of preoperative molecular-based diagnosis of follicular carcinoma has been long expected. We found that quantification of the trefoil factor 3(TFF3)/galectin-3 mRNA ratio in thyroid tumor cells is a useful tool for distinction between follicular adenomas and carcinomas. Because ABND can be performed without any severe invasion to the patients, in the near future, when more reliable systems of quantitative RNA analysis have been developed, ABND will probably become one of the standard tests for preoperative diagnosis of thyroid carcinoma.
Biopsy, Needle↗
Ubiquitous expression of galectin-3 mRNA in benign and malignant thyroid tumors.
We measured the relative expression levels of galectin-3 mRNA to beta-actin mRNA in normal thyroid tissues, thyroid tumor tissues and thyroid-derived fibroblasts. Galectin-3 mRNA was expressed ubiquitously in both benign and malignant thyroid tumors. Although a significant increase in its expression was observed in papillary carcinomas, no significant difference was observed between follicular carcinomas and adenomas. In contrast to the previous optimistic reports using immunohistochemical analysis of the galectin-3 protein expression, these results demonstrate that galectin-3 mRNA may not be a suitable target for molecular-based diagnosis of thyroid carcinomas.
Adenocarcinoma, Follicular↗
Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders.
There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders. Using a sensitive radioligand assay, we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1, 34.4%), mu-opioid receptor (OPRM1, 13.1%), 5-hydroxytryptamine receptor 1A (HTR1A, 7.4%), and dopamine receptor D2 (DRD2, 4.9%) in 122 psychiatric patients. Positive antibodies to CHRM1 were found in 34.1%, 34.9%, 33.3%, and 9.1% of patients with schizophrenic disorders (n=44), mood disorders (n=63), other psychiatric disorders (n=15) and autoimmune diseases (n=33), respectively. All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A. Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome.
Adult↗